PROJECT SUMMARY Successful memory retrieval is one of the most important functions in our brain. Numerous studies have shown that hippocampal-entorhinal (HPC-EC) circuits play crucial roles in encoding and retrieval of specific episodic memories. Many human patients who suffer from Alzheimer's disease, dementia and the broad spectrum of psychosis, including schizophrenia, show various ranges of memory deficits along with the HPC-EC damage. However, little is known about how specific memories are accessed and formed into meaningful memories to accomplish given tasks, especially at the systems level. This proposal focuses on the neural dynamics for successful memory access and retrieval during episodic working memory tasks to elucidate the neural circuit mechanism in the hippocampal-cortical (HPC-CTX) network. My long-term goal is to elucidate neural dynamics during psychotic states and to establish novel early-stage diagnostic measurements / analyses in human patients that are hinted at by in vivo recordings in animal models. I have previously demonstrated two forms of memory access in the HPC-EC circuits that are crucial during episodic memory tasks. The first form is called `gamma phase synchrony', which was observed during the running period of a spatial working memory task when the animal was about to make turns at the junction point of a T-maze. The second form is called an `extended interregional ripple burst', a memory replay event that is made of alternating chains of burst activities within HPC- EC network during quiet awake or stopping periods on a large running maze. These two forms of memory access turned out to be crucial for subsequent spatial working memory behavior. However, the circuit mechanism or memory contents during these neural activities under different behavioral states are still unknown. Revealing such memory contents during the memory access period will be crucial to understanding of how exactly our memory system works. We hypothesize that (i) the content of burst activities between HPC and EC index each other to retrieve longer episodes as an inter-regional communication during the off-line state and then (ii) the previously potentiated or activated group of neurons gets briefly activated in gamma phase synchrony during the active state to successfully execute the memory process. We will test three hypotheses in this proposal by combining transgenic mouse technology, circuit specific optogenetics, large-scale in vivo electrophysiology, and a spatial working memory task in mice. The first two specific aims will focus on neural content decoding during two forms of memory access and the third specific aim will investigate whether the two distinct forms of memory process have a causal relationship on the successful accession of memory in the HPC-EC network.